Biology subjects

Landerer, C.

Publications and source records attributed to Landerer, C..

7 recordsLinked to original sources

bioRxiv2026

Amino acid and codon usage explain amino acid misincorporation rates across the tree of life

Protein translation is an error-prone process resulting in a random population of altered protein sequences in every cell. Here, we analyzed thousands of publicly available mass spectrometry datasets to detect amino acid misincorporations and quantify error rates in 14 model organisms. We find that overall error rates and the patterns of codon to amino acid error rates correlate across species. We estimate that on average 1-2% of protein molecules in a cell harbor a misincorporation, whereas this proportion can reach 10% for long proteins. Highly expressed and very long proteins have lower error rates, indicating evolutionary selection on codon usage to reduce the cost of translation errors. While both codon-anticodon mispairing and tRNA mischarging contribute to misincorporations, we estimate that [~]70% of misincorporation events are due to mispairing. The more frequent an amino acid in the proteome, the more likely it is misincorporated (r = 0.53), likely because frequent amino acids are abundant in the cell, increasing the rate of mischarging, and have abundant tRNAs, leading to increased mispairing. Overall, we find that amino acid and codon usage explain error rates. The conserved patterns of amino acid misincorporations from bacteria to humans suggest universal mechanisms driving translational fidelity.

bioinformatics↗

bioRxiv2025

Ribosomal frameshifting is a carefully tuned modifier of proteins

Ribosomal frameshifting, occurring during protein translation, is one of the most consequential recoding events, as it leads to large changes to the protein sequence. However, beyond a few well-characterized cases, its prevalence and consequences across organisms remain poorly understood. To address this, we modeled and experimentally tested frameshifting and systematically characterized its evolutionary impact. We developed SLIPPERRS, a mechanistic model that identifies "slippery" frameshift sites achieving [~]70% accuracy. Building on SLIPPERS predictions and on our mass spectrometry and fluorescence-based assay, we characterized 165 short mRNA sequences. We identified dozens of novel sites with frameshift probabilities that often exceed those of known programmed frameshift cases, and found evidence for both translocation and decoding mechanisms. In Gammaproteobacteria, an average of [~]100 genes per species harbor frameshifting sites, which alter proteins by truncating, extending, and fusing canonical proteins. We detect selection for shorter and less disordered frameshifted proteins to mitigate their deleterious impact. We found negative correlation between GC-content and the occurrence of frameshifting sites. In GC-rich bacteria, where frameshift products are expected to be particularly long and disordered, there is selection for cryptic stop codons. While frameshifting is prevalent and expands protein diversity, it is carefully tuned to avoid its harmful consequences.

biochemistry↗

bioRxiv2022

Evolutionary impact of codon specific translation errors at the proteome scale

Errors in protein synthesis can lead to non-genetic phenotypic mutations, which contribute to generating a wide range of protein diversity. There are currently no methods to measure proteome-wide amino acid misincorporations in a high-throughput fashion, limiting their detection to specific sites and few codon-anticodon pairs. Therefore, it has been technically challenging to estimate the evolutionary impact of translation errors. Here, we developed a computational pipeline, integrated with a novel mechanistic model of translation errors, which can detect translation errors across organisms and conditions. We revealed hundreds of thousands of amino acid misincorporations and a rugged error landscape in datasets of E. coli and S. cerevisiae. We provide proteome-wide evidence of how codon choice can locally reduce translation errors. Our analysis indicates that the translation machinery prevents strongly deleterious misincorporations while allowing for advantageous ones, and the presence of missing tRNAs would increase codon-anticodon cross-reactivity and misincorporation error rates.

evolutionary biology↗

bioRxiv2022

A conserved and tunable mechanism for the temperature-controlled condensation of the translation factor Ded1p

Heat shock promotes the assembly of translation factors into condensates to facilitate the production of stress-protective proteins. How translation factors detect heat and assemble into condensates is not well understood. Here, we investigate heat-induced condensate assembly by the translation factor Ded1p from five different fungi, including Ded1p from Saccharomyces cerevisiae. Using targeted mutagenesis and in vitro reconstitution biochemistry, we find that heat-induced Ded1p assembly is driven by a conformational rearrangement of the folded helicase domain. This rearrangement determines the assembly temperature and the assembly of Ded1p into nanometer-sized particles, while the flanking intrinsically disordered regions engage in intermolecular interactions to promote assembly into micron-sized condensates. Using protein engineering, we identify six amino acid substitutions that determine most of the thermostability of a thermophilic Ded1p ortholog, thereby providing a molecular understanding underlying the adaptation of the Ded1p assembly temperature to the specific growth temperature of the species. We conclude that heat-induced assembly of Ded1p into translation factor condensates is regulated by a complex interplay of the structured domain and intrinsically disordered regions which is subject to evolutionary tuning.

biochemistry↗

bioRxiv2021

The novel Rab5 effector FERRY links early endosomes with the translation machinery

Localized translation is vital to polarized cells and requires precise and robust distribution of different mRNAs and ribosomes across the cell. However, the underlying molecular mechanisms are poorly understood and important players are lacking. Here we show that the novel Rab5 effector Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY, FERRY complex recruits mRNAs and ribosomes to early endosomes, through direct mRNA interaction. FERRY displays preferential binding to certain groups of transcripts, including mRNAs encoding mitochondrial proteins. Deletion of FERRY subunits reduces the endosomal localization of transcripts in cells and has a significant impact on mRNA and protein levels. Clinical studies show that genetic disruption of FERRY causes severe brain damage. We found that, in neurons, FERRY co-localizes with mRNA on early endosomes and mRNA loaded FERRY-positive endosomes are in close proximity of mitochondria. FERRY thus transforms endosomes into mRNA carriers and plays a key role in regulating mRNA distribution and transport.

cell biology↗

bioRxiv2019

Decomposing Mutation and Selection to Identify Mismatched Codon Usage

For decades, codon usage has been used as a measure of adaptation for translational efficiency and translation accuracy of a genes coding sequence. These patterns of codon usage reflect both the selective and mutational environment in which the coding sequences evolved. Over this same period, gene transfer between lineages has become widely recognized as an important biological phenomenon. Nevertheless, most studies of codon usage implicitly assume that all genes within a genome evolved under the same selective and mutational environment, an assumption violated when introgression occurs. In order to better understand the effects of introgression on codon usage patterns and vice versa, we examine the patterns of codon usage in Lachancea kluyveri, a yeast which has experienced a large introgression. We quantify the effects of mutation bias and selection for translation efficiency on the codon usage pattern of the endogenous and introgressed exogenous genes using a Bayesian mixture model, ROC SEMPPR, which is built on mechanistic assumptions about protein synthesis and grounded in population genetics. We find substantial differences in codon usage between the endogenous and exogenous genes, and show that these differences can be largely attributed to differences in mutation bias favoring A/T ending codons in the endogenous genes while favoring C/G ending codons in the exogenous genes. Recognizing the two different signatures of mutation bias and selection improves our ability to predict protein synthesis rate by 42% and allowed us to accurately assess the decaying signal of endogenous codon mutation and preferences. In addition, using our estimates of mutation bias and selection, we identify Eremothecium gossypii as the closest relative to the exogenous genes, providing an alternative hypothesis about the origin of the exogenous genes, estimate that the introgression occurred [~] 6 x 108 generation ago, and estimate its historic and current selection against mismatched codon usage. Our work illustrates how mechanistic, population genetic models like ROC SEMPPR can separate the effects of mutation and selection on codon usage and provide quantitative estimates from sequence data.

evolutionary biology↗

bioRxiv2017

Population Genetics Based Phylogenetics Under Stabilizing Selection for an Optimal Amino Acid Sequence: A Nested Modeling Approach

We present a new phylogenetic approach SelAC (Selection on Amino acids and Codons), whose substitution rates are based on a nested model linking protein expression to population genetics. Unlike simpler codon models which assume a single substitution matrix for all sites, our model more realistically represents the evolution of protein coding DNA under the assumption of consistent, stabilizing selection using cost-benefit approach. This cost-benefit approach allows us generate a set of 20 optimal amino acid specific matrix families using just a handful of parameters and naturally links the strength of stabilizing selection to protein synthesis levels, which we can estimate. Using a yeast dataset of 100 orthologs for 6 taxa, we find SelAC fits the data much better than popular models by 104-105 AICc units. Our results indicate there is great potential for more accurate inference of phylogenetic trees and branch lengths from already existing data through the use of nested, mechanistic models. Additional parameters estimated by SelAC indicate that a large amount of non-phylogenetic, but biologically meaningful, information can be inferred from exisiting data. For example, SelAC prediction of gene specific protein synthesis rates correlates well with both empirical (r=0.33-0.48) and other theoretical predictions (r=0.45-0.64) for multiple yeast species. SelAC also provides estimates of the optimal amino acid at each site. Finally, because SelAC is a nested approach based on clearly stated biological assumptions, future modifications, such as including shifts in the optimal amino acid sequence within or across lineages, are possible.

evolutionary biology↗